Current evidence indicates that increasing numbers of infants are born to HIV-infected mothers each year. HIV-infected children may be small-for-gestational-age, growth restricted (gr), or appear thin and wasted at birth. Our prior studies have shown that inoculation of fetal macaques with pathogenic SIVMAC251 during the early second trimester results in significant gr and a rapid postnatal disease course. Further studies were conducted with a focus on fetal growth and viral pathogenesis. Twenty-six fetuses were inoculated in utero via ultrasound-guidance with uncloned pathogenic sivmac251 or vehicle during the second or third trimesters (gestational day [gd] 65, 110, or 130), sonographically monitored weekly (biometrics, blood flow), then necropsied at incremental timepoints post-infection. Peripheral blood hematologic (complete blood counts, clinical chemistries), immunologic (immunophenotyping), and endocrine studies (insulin-like growth factor [IGF], IGF binding proteins) were conducted. Severe intrauterine gr, oligohydramnios, and aberrant lymphocyte counts were noted for fetuses infected on gd 65. Less severe effects were detected for fetuses inoculated at the later timepoints, with severity dependent upon the length of siv infection in utero. IGF studies indicated significant reductions in IGF-I and elevated immunoreactive levels of IGFBP-3 in infected fetuses during the third trimester. Parallel studies conducted with four fetuses infected on gd 65 with a nonpathogenic, molecularly cloned virus (sivmac1a11) resulted in normal fetal growth, with no effects on hematopoiesis or IGF/IGFBP levels, and no evidence of clinical disease. Taken together, these studies have shown that (1) infection of fetuses during the early second trimester with an uncloned pathogenic strain of siv results in severe gr and a disruption in the molar ratio of IGF:IGFBP-3, and (2) outcome of fetal SIV infection is determined by the timing of infection and the virulence of the viral inoculum.